JP6337266B2 - Polymorphic form - Google Patents

Description

  The present invention relates to 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3- c) A new crystalline form of pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide. More specifically, the present invention relates to L-tartrate polymorph forms of this compound, and methods for making such polymorphs, compositions containing such polymorphs, and Regarding use.

  This compound, 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c ] Pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide is disclosed in WO97 / 024369 as a growth hormone secretagogue and ghrelin receptor agonistic activity . This compound has the common name capromorelin and has been developed in the clinical stage. A method for the synthesis of this compound is also disclosed in EP-1031575.

  However, 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] Neither the crystals of pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide or mixtures of crystal forms are known to the public.

WO97 / 024369 EP-1031575

  As is well known to those skilled in the art, finding or manufacturing crystals or crystalline forms in drug development from a variety of perspectives, including drug formulation and manufacture, is a desirable goal (Byrn SR et al., Solid-State Chemistry of Drugs 2nd edition, pp 3-43 and 461-503, 1999, SSCI, Inc.).

  Along this line, 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, disclosed by Pfizer in 1997 (WO97 / 024369) , 4,6,7-Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide Great efforts have been made to make or manufacture.

Despite such great efforts, a pharmaceutically suitable crystalline form of the compound has not yet been identified.
As a result of thorough and careful investigation, the inventors of the present invention have succeeded in finding the conditions for producing the crystals, and thereby the long-awaited crystalline form (polymorphic form I) is obtained by converting the compound into L-tartrate. Can be provided.

  Polymorph Form I has been identified as disclosed in the examples of the present invention.

  The present invention is manufactured in a simple, economical and reproducible way, for example, filterability, ease of handling, easy purity control, stability and non-hygroscopicity, etc. 2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [ The object is to provide a pharmaceutically suitable crystalline form of 4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide. It is also an object of the present invention to provide a method for producing such polymorphic forms, compositions and uses comprising such polymorphic forms.

That is, the present invention provides the following:
[1] CuKα with main peaks at 2-θ ° including 4.4, 10.2, 12.5, 13.2, 13.7, 16.4, 16.6, 18.5, 19.3 and 21.7 (where each peak has an error range of +/− 0.2 °) 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-L-tartrate] characterized by the powder X-ray diffraction pattern (PXRD) obtained by irradiation with radiation -2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide Polymorphic form I;

[2] L-Tartrate 2-amino-N- [2- (3a- (R)-] according to [1], which is further characterized by differential scanning calorimetry (DSC) showing an endothermic event at about 177 ° C Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2 -Oxo-ethyl] -isobutyramide polymorph I

[3] 3349, 3107, 3036, 2983, 2870, 2770, 2526, 1705, 1662, 1625, 1531, 1454, 1442, 1220, 1132, 1109, 1089, and 704 cm ^-1 (where each peak is + / L-tartaric acid 2-amino-N-[-] according to [1] or [2], which is further characterized by an infrared (IR) spectrum (KBr) showing an absorbance band at −2 cm ⁻¹ ) 2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- Polymorph Form I of (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide;

[4] L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, described in any one of [1] to [2], Polymorphic form of 3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide A pharmaceutical composition comprising I together with one or more pharmaceutically acceptable excipients;

[5] L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3] described in any one of [1] to [3] for use as a drug -Oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyl Amide polymorphic form I;

[6] L-tartaric acid 2 as described in any one of [1] to [3] in the manufacture of a medicament for curative, palliative or prophylactic treatment of pathological conditions mediated by ghrelin receptor agonistic activity -Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine-5 -Yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph I, or use of a pharmaceutical composition according to [4];

[7] A method for treating a disease state mediated by ghrelin receptor activity, which is described in any one of [1] to [3] in an effective amount for animals including humans in need of such treatment. 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3- c) pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph I, or administering a pharmaceutical composition according to [4] how to;

[8] 2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7 in an organic solvent (preferably ethyl acetate) -Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide with alcohol (preferably methyl alcohol, ethyl alcohol and isopropyl L-Tartrate 2-amino-N- [2- (3a] described in [1]-[3], comprising a step of exposing to conditions of L-tartaric acid in an alcohol, more preferably methyl alcohol and isopropyl alcohol) -(R) -Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R)- Process for preparing polymorph Form I of benzyloxymethyl-2-oxo-ethyl] -isobutyramide;

[9] 2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4] in ethyl acetate , 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide under conditions of L-tartaric acid in methanol or isopropyl alcohol 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3 L-tartrate as described in any one of [1] to [3] , 3a, 4,6,7-Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide I How to manufacture.

[10] 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a] selected from the group consisting of methyl alcohol, ethyl alcohol, and isopropyl alcohol , 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide, 1]-[3] L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, Polymorph Form I of 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide is prepared Method.

[11] 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4] in methanol or isopropanol , 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide, which comprises exposing 2-amino tartrate as described in [10] -N- [2- (3a- (R) -Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl ) -1- (R) -Benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph Form I.

As mentioned above, the object is to discover or prepare crystals or crystal forms having unpredictably superior physicochemical properties in drug development from various perspectives including drug formulation and manufacture. Surprisingly, this purpose is based on L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7- The crystalline polymorphic form of hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide (named polymorphic form I) It has become clear that the present invention has been achieved.
Despite the great efforts of those skilled in the art, no pharmaceutically relevant crystalline form of the compound has been identified so far.

  All polymorphs of the present invention are superior to the white solids disclosed in the prior art WO97 / 024369 and have unexpected advantages. Polymorph Form I has been found to be more stable than the solids disclosed in the prior art WO97 / 024369.

  Furthermore, it has been found that the polymorphic forms of the present invention are applicable to large scale synthesis. They have acceptable solid state properties for the development of solid dosage forms.

FIG. 1 shows the L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4 , 3-c] Pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph Form I PXRD pattern.

  Thus, the present invention provides the main peaks at 2-θ ° 4.4, 10.2, 12.5, 13.2, 13.7, 16.4, 16.6, 18.5, 19.3 and 21.7, where each peak has an error range of +/− 0.2 °. L-Tartaric acid 2-amino-N- [2- (3a- (R) -benzyl-2-methyl) crystalline characterized by powder X-ray diffraction pattern (PXRD) obtained by irradiation with CuKα radiation containing -3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] Providing polymorphic form I of isobutyramide;

  2-amino-N- [2- (3a- (R) -benzyl-2-methyl-L-tartrate] L-tartrate further characterized by differential scanning calorimetry (DSC) showing an endothermic thermal event at about 177 ° C 3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl]- Polymorphic form I of isobutyramide;

3349, 3107, 3036, 2983, 2870, 2770, 2526, 1705, 1662, 1625, 1531, 1454, 1442, 1220, 1132, 1109, 1089 and 704 cm ^-1 (the peak where the +/- 2 cm ^- Polymorphic form I as described above, further characterized by an infrared (IR) spectrum (KBr) exhibiting an absorbance band at an error range of ¹ ;

  As a further aspect of the present invention, the L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7, -Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph Form I is provided for use as a medicament To do.

  As a further aspect of the present invention, the L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7, -Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorphic form I involves ghrelin receptor agonists Curative, prophylactic, or palliative treatment of any disease that involves 1) gastrointestinal disorders, 2) disorders due to loss of appetite, appetite suppression, or reduced food intake, and 3) diseases involving high gastric acid secretion For use in the manufacture of a medicament.

  Gastrointestinal disorders are postoperative ileus, gastric insufficiency, opioid-induced bowel dysfunction, chronic intestinal pseudoobstruction, acute colonic pseudoobstruction (Ogilby syndrome), intestinal motility disorder, short bowel syndrome, vomiting, constipated irritable bowel syndrome (IBS), chronic constipation, functional dyspepsia, cancer-related dyspepsia syndrome, graft-versus-host disease, delayed gastric emptying, gastrointestinal disorders or delayed gastric emptying associated with other disease states, status of critical care Selected from the group consisting of gastrointestinal dysmotility or delayed gastrointestinal tract, gastrointestinal dysfunction or delayed gastric emptying resulting from treatment with drugs, gastroesophageal reflux disease (GERD), gastric ulcer, gastroenteritis and Crohn's disease Can do.

  Disorders caused by loss of appetite, loss of appetite, or decreased food intake include cachexia, where cachexia is cancer, chronic heart failure, acquired immune deficiency syndrome (AIDS), kidney disease Including those induced by muscular dystrophy or aging.

  Examples of diseases involving high gastric acid secretion include acid deficiency.

  In another aspect of the invention, a therapeutically effective amount of the L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3, 3a, 4,6,7-Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph Form I Any disease involving ghrelin receptor agonists, including administration to animals, including humans in need of such treatment, especially 1) gastrointestinal disorders, 2) anorexia, appetite suppression, or reduced food intake 3) provide therapeutic methods in curative, prophylactic, or palliative treatment of disorders involving high gastric acid secretion.

  L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4, The polymorphic form I of 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide is a common pathology mediated by ghrelin receptor agonist activity It is useful for proper treatment.

  L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4, 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph I includes 1) gastrointestinal disorders, 2) anorexia, appetite suppression, Or it may be useful in the treatment of disorders or conditions selected from the group consisting of disorders that result in reduced food intake, and 3) diseases that involve high gastric acid secretion.

  2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine- A synthetic route for the preparation of 5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide is described in WO 97/024369 and the experimental part below.

  L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c ] Polymorph Form I of] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide is a compound of 2-amino-N- [] in an organic solvent such as ethyl acetate. 2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- It can be prepared by crystallization by adding an alcohol (eg, methyl alcohol) solution of L-tartaric acid to a solution of (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide.

  Organic solvents that can be used for crystallization of polymorph Form I include carboxylic acid esters such as ethyl acetate, and alcohols such as methyl alcohol, ethyl alcohol, and isopropyl alcohol.

  L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4, 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph I can be used alone or with one or more other drugs. It can be administered in combination (or as any combination thereof). In general, they are administered as a formulation with one or more pharmaceutically acceptable excipients. The term “excipient” is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.

  Accordingly, as a further aspect of the present invention, L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro -Pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph I and one or more suitable A pharmaceutical composition comprising the form is provided. The composition is suitable for the treatment of conditions mediated by ghrelin receptor activity.

  L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4, The weight purity of polymorph Form I of 3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide is not limited, but preferably Essentially pure polymorphic forms can be used in specific embodiments of the invention.

For the avoidance of doubt, the expression “essentially pure” as used herein means at least 90% by weight purity. More preferably, “essentially pure” means at least 95% by weight purity, and most preferably at least 98% by weight purity.
Reference herein to “treatment” includes reference to curative, palliative and prophylactic treatment.

  For non-human animal administration, the term “pharmaceutical” as used herein may be replaced by “veterinary”.

  Pharmaceutical compositions suitable for delivery of the polymorphic forms of the present invention and methods for their production will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995); Polymorphism by Rolf Hilfiker: In the Pharmaceutical Industry (John Wiley & Sons, 2006).

Oral Administration The polymorphic forms of the present invention can be administered orally. Oral administration may include swallowing so that the compound enters the gastrointestinal tract and / or buccal, lingual or sublingual administration where the compound enters the bloodstream directly from the mouth.

  Formulations suitable for oral administration are solid, semi-solid and liquid systems such as tablets; soft or hard capsules containing multi- or nano-particles, liquids or powders; lozenges (eg liquid filling); chewing agents; Gels; rapid dispersion dosage forms; coatings; oval dosage forms; sprays; and cheek or mucoadhesive patches.

  Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations are used as fillers in soft or hard capsules (eg made of gelatin or hydroxypropylmethylcellulose) and are typically carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils As well as one or more emulsifiers and / or suspending agents. Liquid formulations can also be produced by reconstitution of solids obtained, for example, from sachets.

  The polymorphic form I of the present invention can also be used in fast dissolving, rapidly disintegrating dosage forms as described, for example, in Liang and Chen, Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001).

  For tablet dosage forms, depending on dose, the drug may make up from 1% to 80% by weight of the dosage form, more typically from 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch And sodium alginate. Generally, the disintegrant comprises 1% to 25%, preferably 5% to 20% by weight of the dosage form.

Binders are commonly used to impart tackiness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets can be diluted with diluents such as lactose (monohydrate, spray-dried monohydrate, and anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate Can include Japanese products.
Tablets may also optionally contain surface active agents, such as sodium lauryl sulfate and polysorbate 80, and lubricants, such as silicon dioxide and talc. When present, surfactants may comprise 0.2% to 5% by weight of the tablet and lubricants may comprise 0.2% to 1% by weight of the tablet.

Tablets generally also contain a lubricant, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant generally comprises 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight of the tablet.
Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives and taste masking agents.
Exemplary tablets have up to about 80% drug, about 10% to about 90% binder, about 0% to about 85% diluent, about 2% to about 10% disintegrant. And about 0.25% to about 10% by weight of a lubricant.

  Tablet formulations may be formed into tablets by being compressed directly or by roller. The tablet formulation or a portion of the formulation can alternatively be wet, dry or melt granulated, melt set or extruded prior to tableting. The final formulation includes one or more layers and may or may not be coated; it can be further encapsulated.

  Tablet formulations are described in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets, Vol. 1 (Marcel Dekker, New York, 1980); Larry L. Augsburger and Hoag W. Stephen, Pharmaceutical Dosage Forms: Tablets, Third Edition, Volume 2: Rational Design and Formulation (Informa Healthcare, published June 2008).

  Consumable oral films for human or veterinary use are typically flexible water-soluble or water-swellable thin film dosage forms that are rapidly soluble or mucoadhesive It typically includes polymorphic forms of the invention, film-forming polymers, binders, solvents, humectants, plasticizers, stabilizers or emulsifiers, viscosity modifiers and solvents. Some components of the formulation may achieve more than one function.

  Polymorph Form I of the present invention can be water soluble or water insoluble. The water soluble compound may typically comprise 1% to 80% by weight, more typically 20% to 50% by weight of solute. Less soluble compounds may contain a larger percentage of the composition, i.e. typically up to 88 wt% solute. Alternatively, the polymorphic form I of the present invention can be in the form of multiparticulate beads.

  The film-forming polymer may be selected from natural polysaccharides, proteins or synthetic hydrocolloids, but is typically present in the range of 0.01 to 99% by weight and more typically in the range of 30 to 80% by weight.

  Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, salivary stimulants, coolants, co-solvents (eg oils), emollients, leavening agents, Examples include foaming agents, surfactants, and taste masking agents.

  The coatings of the present invention are typically produced by evaporating and drying an aqueous film coated on a peelable backing support or paper.

  This can be done in a drying oven or tunnel, typically in a combined coater dryer, or by freeze drying or vacuum processing.

  Solid formulations for oral administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

  Suitable modified release formulations for the purposes of the invention are described in US Pat. No. 6,106,864. Details of other suitable release techniques such as high energy dispersion and permeability and coated particles can be found in Verma et al., Pharmaceutical Technology On-line, 25 (2), 1-14, (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298.

Parenteral Administration Polymorph Form I of the present invention can also be administered directly into the bloodstream, muscle, or internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes and infusion techniques.

  Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffers (preferably having a pH of 3-9), but for some applications they are Can be more suitably formulated as a sterile non-aqueous solution or as a dry form for use with a suitable vehicle such as sterile water, pyrogen-free water.

  For example, the manufacture of parenteral formulations under sterile conditions by lyophilization can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

  Formulations for parenteral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release. Thus, the polymorph Form I of the present invention can be formulated as a solid, semi-solid or thixotropic liquid for administration as a suspension or as an embedded depot that provides controlled release of the active compound. Examples of such formulations include drug-coated stents and semi-solids and suspensions of drug-filled poly (lactic-co-glycolic acid) (PLGA) microspheres.

Topical Administration Polymorph Form I of the present invention can also be administered topically, dermally (intradermally) or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, sweat-removing powders, finishes, foaming agents, films, skin patches, wafers, grafts, sponges, fibers, bandages and micros An emulsion is mentioned. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers can be incorporated (see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999)).

  Other means of topical administration include electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (eg Powderject ™, Bioject ™ etc.) injection Delivery by. Topical administration can also be accomplished using a patch, such as a transdermal iontophoretic patch.

  Formulations for topical administration can be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

  The polymorphic form I of the present invention is typically a dry powder from a dry powder inhaler (alone, as a mixture, eg, in a dry formulation with lactose, or mixed with, for example, a phospholipid, eg, phosphatidylcholine). Use of a suitable propellant, eg 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, in the form of component particles) As an aerosol spray from pressurized containers, pumps, sprays, atomizers (preferably nebulizers that use electrohydrodynamics to generate a fine mist) or nebulizers with or without Alternatively, it can be administered as a nasal spray, intranasally or by inhalation. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

  Pressurized containers, pumps, sprays, nebulizers or inhalers disperse, solubilize or release active ingredients, propellants as solvents, and any surfactants such as sorbitan trioleate, oleic acid or oligolactic acid For extension, it contains a solution or suspension of the polymorphic form of the invention containing, for example, ethanol, aqueous ethanol, or a suitable alternative.

  Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This can be achieved by any suitable comminuting method, such as vortex jet milling, fluid bed jet milling, supercritical fluid processing to produce nanoparticles, high pressure homogenization, or spray drying.

  Capsules (eg made from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in inhalers or sprayers are suitable for compounds of the invention, suitable powder bases such as lactose or starch, and performance modifiers An agent, such as a powder mixture of L-leucine, mannitol or magnesium stearate, may be formulated. Lactose can be anhydrous or in the form of a monohydrate, but is preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

  A suitable solution formulation for use in a nebulizer using electrohydrodynamics to generate a fine mist contains 1 μg to 20 mg of the compound of the invention per operation and an operating volume of 1 μL to 100 Can vary up to μL. A typical formulation may comprise a polymorphic form according to the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

  Suitable flavoring agents such as methanol and levomethanol, or sweetening agents such as saccharin or sodium saccharin may be added to the formulations of the invention intended for inhalation / intranasal administration.

  Formulations for inhalation / intranasal administration may be formulated for immediate and / or modified release, for example using PLGA. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

  In the case of dry powder inhalers and aerosols, the dosage unit is determined by a valve that delivers a metered amount. The unit according to the invention is typically 1 μg to 20 mg of L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a , 4,6,7-Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph Form I Adjusted to administer a measured dose or “puff”. The total daily dose typically ranges from 1 μg to 100 mg, which can be administered in a single dose or, more usually, as divided doses throughout the day.

Rectal / Intravaginal Administration Polymorphic Form I of the present invention can be administered rectally or vaginally, for example in the form of suppositories, pessaries or enemas. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.

  Formulations for rectal / vaginal administration may be formulated for immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

Ocular / Ear Administration Polymorph Form I of the present invention can also be administered directly to the eye or ear, typically in the form of a finely divided suspension or solution in isotonic pH-adjusted sterile saline. Other formulations suitable for ocular and otic administration include ointments, gels, biodegradable (eg absorbable gels, sponges, collagen) and non-biodegradable (eg silicone) implants, wafers, lenses and granular or vesicular forms Examples include systems such as niosomes or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers such as gellan gum are incorporated with preservatives such as benzalkonium chloride sell. Such formulations can also be delivered by iontophoresis.

  Formulations for ocular / ear administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

Other Techniques Polymorph Form I of the present invention is for use in any of the above modes of administration to improve their solubility, dissolution rate, taste masking properties, bioavailability and / or stability. In addition, it can be combined with soluble polymeric substances such as cyclodextrins and their appropriate derivatives, or polyethylene glycol-containing polymers.
For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, cyclodextrin can be used as an auxiliary additive, ie as a carrier, diluent or solubilizer. The most commonly used for these purposes are α-, β- and γ-cyclodextrins, examples of which are described in WO 91/11172, WO 94/02518, WO 98/55148 and Evrard, B. et al., Journal of Controlled Release 96 (3), pp. 403-410, 2004.

Dosage To treat or prevent a condition mediated by ghrelin receptor activity, a suitable dosage level of polymorphic Form I of the present invention is about 0.0001-1000 mg per day as active compound, preferably 1 day. About 0.001 to 100 mg per day, more preferably about 0.005 to 50 mg per day, most preferably 1 to 50 mg per day. The compound can be administered on a regimen of 1 to 4 times per day. However, in some cases, doses outside these limits can be used.

  These dosages are based on an average human subject having a weight of about 60 kg to 70 kg. The physician can readily determine doses for subjects whose weight falls outside this range, such as infants and the elderly. For the avoidance of doubt, references herein to “treatment” include references to curative, palliative and prophylactic treatment.

  The polymorphic form I of the present invention may also comprise another pharmacologically active compound, or two or more other pharmacologically active compounds, particularly for the treatment of conditions mediated by ghrelin receptor activity. And can be arbitrarily combined. For example, the polymorphic form I of the present invention as described above may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:

Opioid analgesics such as morphine, heroin, hydromorphone, oxymorphone, levorphanol, levalorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalolphine, naltrexone, butrenorphine, Butorphanol, nalbuphine, or pentazocine;

Non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflucinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, Meloxicam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmethine, or zomepirac;

-Barbituric acid sedatives, such as amobarbital, aprobarbital, butabarbital, butarbital, mehobarbital, metalbital, methohexital, pentobarbital, phenobarbital, secobarbital, tarbutal, thiamylal, or thiopental;

A benzodiazepine having a sedative effect, such as chlordiazepoxide, chlorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

An H1 antagonist having a sedative effect, such as diphenhydramine, pyrilamine, promethazine, chlorpheniramine, or chlorcyclidine;
Sedatives such as glutethimide, meprobamate, methacarone, or dichlorarphenazone;

Skeletal muscle relaxants, such as baclofen, carisoprodol, chlorzoxazone, cyclobenzaprine, metocarbamol, or orphenadrine;

NMDA receptor antagonists such as dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmole) Finan), ketamine, memantine, pyrroloquinoline quinine, cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®: combination preparation of morphine and dextromethorphan), topiramate, Perazine hotels containing neramexane, or NR2B antagonist, such as ifenprodil, traxoprodil, or (-)-(R) -6- {2- [4- (3-fluorophenyl) -4-hydroxy-1-piperidinyl] -1-hydroxyethyl-3,4-dihydro-2 ( H) - quinolinone;

Alpha adrenergic agonists such as doxazosin, tamsulosin, clonidine, guanfacine, dexmedetomidine, modafinil, or 4-amino-6,7-dimethoxy-2- (5-methane-sulfonamide-1,2,3,4 Tetrahydroisoquinol-2-yl) -5- (2-pyridyl) quinazoline;

• Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline;

Anticonvulsants such as carbamazepine, lamotrigine, topiramate, or valproate;

Tachykinin (NK) antagonists, specifically NK-3, NK-2, or NK-1 antagonists such as (αR, 9R) -7- [3,5-bis (trifluoromethyl) benzyl] -8,9,10,11-tetrahydro-9-methyl-5- (4-methylphenyl) -7H- [1,4] diazosino [2,1-g] [1,7] -naphthyridine-6-13 -Dione (TAK-637) (herein the symbol "α" may be described as "alpha"), 5-[[(2R, 3S) -2-[(1R) -1- [3 , 5-Bis (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4-morpholinyl] -methyl] -1,2-dihydro-3H-1,2,4-triazol-3-one ( MK-869), aprepitant, ranepitant, da Pitanto, or 3-[[2-methoxy-5- (trifluoromethoxy) phenyl] -methylamino] -2-phenylpiperidine (2S, 3S);

• Muscarinic antagonists such as oxybutynin, tolterodine, propiverine, trospium chloride, darifenacin, solifenacin, temiverine, and ipratropium;

A COX-2 selective inhibitor, such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etlicoxib, or lumiracoxib;

Coal tar analgesics, specifically paracetamol;

Neuroleptic drugs such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindol, aripiprazole, sonepiprazole, bronanserin, iloperidone , Perospirone, lacloprid, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindrole, eprivanserin, osanetant, rimonabant, meclinerant, Miraxion (registered trademark), or salizotan;

A vanilloid receptor agonist (eg, resiniferatoxin) or an antagonist (eg, capsazepine);

-Transient receptor potential cation channel subtypes (V1, V2, V3, V4, M8, A1) agonists or antagonists;

Β-adrenergic agonists, such as propranolol;

Local anesthetics such as mexiletine;

Corticosteroids such as dexamethasone;

A 5-HT receptor agonist or antagonist, in particular a 5-HT1B / 1D agonist, such as eletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

5-HT2A receptor antagonists such as R (+)-α- (2,3-dimethoxy-phenyl) -1- [2- (4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907) );

Cholinergic (nicotine) analgesics such as ispronicline (TC-1734), (E) -N-methyl-4- (3-pyridinyl) -3-buten-1-amine (RJR-2403), (R ) -5- (2-azetidinylmethoxy) -2-chloropyridine (ABT-594), or nicotine;

-Tramadol (registered trademark);

PDEV inhibitors such as 5- [2-ethoxy-5- (4-methyl-1-piperazinyl-sulfonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [ 4,3-d] pyrimidin-7-one (sildenafil), (6R, 12aR) -2,3,6,7,12,12a-hexahydro-2-methyl-6- (3,4-methylenedioxyphenyl) ) -Pyrazino [2 ′, 1 ′: 6,1] -pyrido [3,4-b] indole-1,4-dione (IC-351 or tadalafil), 2- [2-ethoxy-5- (4- Ethyl-piperazin-1-yl-1-sulfonyl) -phenyl] -5-methyl-7-propyl-3H-imidazo [5,1-f] [1,2,4] triazin-4-one (Vardenafil), 5- (5-A Til-2-butoxy-3-pyridinyl) -3-ethyl-2- (1-ethyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5 -(5-acetyl-2-propoxy-3-pyridinyl) -3-ethyl-2- (1-isopropyl-3-azetidinyl) -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine-7 -One, 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- [2-methoxyethyl] -2,6-dihydro-7H -Pyrazolo [4,3-d] pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl) amino] -2-[(2S) -2- (hydroxymethyl) pyrrolidin-1-yl] -N- (pyrimidine 2-ylmethyl) pyrimidine-5-carboxamide, 3- (1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo [4,3-d] pyrimidin-5-yl) -N- [2- (1-methylpyrrolidin-2-yl) ethyl] -4-propoxybenzenesulfonamide;

Α-2-delta ligands such as gabapentin, pregabalin, 3-methylgabapentin, (1α, 3α, 5α) (3-amino-methyl-bicyclo [3.2.0] hept-3-yl) -acetic acid, (3S, 5R) -3-Aminomethyl-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-heptanoic acid, (3S, 5R) -3-amino-5-methyl-octane Acid, (2S, 4S) -4- (3-chlorophenoxy) proline, (2S, 4S) -4- (3-fluorobenzyl) -proline, [(1R, 5R, 6S) -6- (aminomethyl) Bicyclo [3.2.0] hept-6-yl] acetic acid, 3- (1-aminomethyl-cyclohexylmethyl) -4H- [1,2,4] oxadiazol-5-one, C- [1- (1H-tetrazole- -Ylmethyl) -cycloheptyl] -methylamine, (3S, 4S)-(1-aminomethyl-3,4-dimethyl-cyclopentyl) -acetic acid, (3S, 5R) -3-aminomethyl-5-methyl-octane Acid, (3S, 5R) -3-amino-5-methyl-nonanoic acid, (3S, 5R) -3-amino-5-methyl-octanoic acid, (3R, 4R, 5R) -3-amino-4, 5-dimethyl-heptanoic acid, and (3R, 4R, 5R) -3-amino-4,5-dimethyl-octanoic acid;

・ Cannabinoids;

A metabotropic glutamate subtype 1 receptor (mGluR1) antagonist;

Serotonin reuptake inhibitors, eg, sertraline, sertraline metabolites demethyl sertraline, fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolites desmethylcitalopram, escitalopram , D, l-fenfluramine, femoxetine, ifoxetine, cyanodotiepin, ritoxetine, dapoxetine, nefazodone, sericlamin, and trazodone;

Noradrenaline (norepinephrine) reuptake inhibitors such as maprotiline, lofepramine, mirtazapine, oxaprotilin, fezolamine, tomoxetine, mianserin, buproprion, buproprion metabolites hydroxybuproprion, nomifensine, and viloxazine (Vivalan®) )), In particular, selective noradrenaline reuptake inhibitors such as reboxetine, specifically (S, S) -reboxetine;

Dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran, And imipramine;

Inducible nitric oxide synthase (iNOS) inhibitors such as S- [2-[(1-Iminoethyl) amino] ethyl] -L-homocysteine, S- [2-[(1-Iminoethyl) -amino ] Ethyl] -4,4-dioxo-L-cysteine, S- [2-[(1-Iminoethyl) amino] ethyl] -2-methyl-L-cysteine, (2S, 5Z) -2-amino-2- Methyl-7-[(1-iminoethyl) amino] -5-heptenoic acid, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) -butyl] thio] -5 -Chloro-3-pyridinecarbonitrile; 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -4-chlorobenzonitrile, (2S, 4R) -2-amino-4-[[ -Chloro-5- (trifluoromethyl) phenyl] thio] -5-thiazolebutanol, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio]- 6- (trifluoromethyl) -3-pyridinecarbonitrile, 2-[[(1R, 3S) -3-amino-4-hydroxy-1- (5-thiazolyl) butyl] thio] -5-chlorobenzonitrile, N- [4- [2- (3-chlorobenzylamino) ethyl] phenyl] thiophene-2-carboxamidine, or guanidinoethyl disulfide;

Acetylcholinesterase inhibitors, such as donepezil;

Prostaglandin E2 subtype 4 (EP4) antagonists such as N-[({2- [4- (2-ethyl-4,6-dimethyl-1H-imidazo [4,5-c] pyridine-1 -Yl) phenyl] ethyl} amino) -carbonyl] -4-methylbenzenesulfonamide, or 4-[(1S) -1-({[5-chloro-2- (3-fluorophenoxy) pyridin-3-yl] ] Carbonyl} amino) ethyl] benzoic acid;

-Leukotriene B4 antagonists such as 1- (3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl) -cyclopentanecarboxylic acid (CP-105696), 5- [2- (2-carboxyethyl) ) -3- [6- (4-Methoxyphenyl) -5E-hexenyl] oxyphenoxy] -valeric acid (ONO-4057), or DPC-11870;

5-lipoxygenase inhibitors such as zileuton, 6-[(3-fluoro-5- [4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl]) phenoxy-methyl] -1 -Methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6- (3-pyridylmethyl), 1,4-benzoquinone (CV-6504);

Sodium channel blockers, eg lidocaine;

Calcium channel blockers such as ziconotide, zonisamide, mibefradil;

A 5-HT3 antagonist, such as ondansetron;
Chemotherapeutic drugs such as oxaliplatin, 5-fluorouracil, leucovorin, paclitaxel;
・ Calcitonin gene-related protein (CGRP) antagonists;
A bradykinin (BK1 and BK2) antagonist;
Voltage-dependent sodium-dependent channel blockers (Na _v1.3 , Na _v1.7 , Na _v1.8 );
・ Voltage-dependent calcium channel blockers (N-type, T-type);
P2X (ion channel type ATP receptor) antagonist;
-Acid sensitive ion channel (ASIC1a, ASIC3) antagonists;
Angiotensin AT2 antagonist;
• Chemokine CCR2B receptor antagonist;
Cathepsin (B, S, K) inhibitors;
-Sigma 1 receptor agonists or antagonists;

  And pharmaceutically acceptable salts and solvates thereof.

  Such a combination exhibits excellent effects including synergistic effects in treatment.

Concomitant medications and kits:
One embodiment of the invention is a combination of a polymorphic form of the invention and a disease drug (which is different from the polymorphic form of the invention).
The “combination” of the present invention can exist as a “fix combination” or “kit of parts combination”. “Fixed combination” is defined as (i) at least one disease drug (which is different from polymorph Form I of the present invention); and (ii) a combination in which polymorph Form I is present in one unit. Is done. “Part combination kit” is defined as (i) at least one disease drug (which differs from the polymorphic form of the present invention); and (ii) polymorphic form I present in multiple units. Is done. The components of the “part combination kit” can be administered simultaneously, sequentially or separately. The molar ratio of the polymorphic form to the disease drug used according to the present invention (which differs from the polymorphic form of the present invention) is from 1: 100 to 100: 1, for example from 1:50 to 50: 1. , Or 1:20 to 20: 1, or 1:10 to 10: 1. The two drugs can be administered separately at the same ratio.

  The present invention relates to 2-amino-N- [2- (L-tartrate) for simultaneous, isolated or sequential use in curative, prophylactic or palliative treatment of pathologies mediated by ghrelin receptor activity. 3a- (R) -Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -Benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph Form I, as well as combinations involving one or more therapeutic agents (eg, those described above).

Examples The following examples are for reference only.

analysis

Powder X-ray diffraction (PXRD)
PXRD analysis is performed using a Rigaku RINT-TTR X-ray powder diffractometer using Cu-Kα radiation. Samples can also be measured under hot / cold conditions using the attachment of a variable-temperature sample holder. The instrument is equipped with a focused X-ray tube. Set tube voltage and amperage to 50 kV and 300 mA, respectively. The divergence and scattering slits were set to 0.5 ° and the receiving slit was set to 0.15 mm. Diffracted radiation is detected with a NaI scintillation detector. A continuous scan of θ-2θ is used at 3 to 40 (2θ °), 4 ° / min (step width 0.02 °). Analyze silicon standards and check machine alignment. Data is collected and analyzed using a Rigaku X-ray system. Samples are prepared for analysis in aluminum sample holders that rotate horizontally at 60 rpm during data acquisition.

Thermogravimetric / differential thermal analysis (TG / DTA)
TG / DTA is performed using a Seiko 6200R system. Place the sample in an aluminum TG / DTA pan. Each sample is heated at a rate of 5 ° C / min to a final temperature of 300 ° C under a nitrogen purge. Indium metal is used as a calibration standard. Reported values are approximate and should therefore be considered approximate.

Differential scanning calorimetry (DSC)
Differential scanning calorimetry (DSC) is performed using a Mettler Toledo DSC822. Place the sample in an aluminum DSC pan and record the weight accurately. The pan is covered with a lid with pinholes and then closed. Each sample is heated at a rate of 5 ° C./min to a final temperature of 220 ° C. under a nitrogen purge. Metal indium is used as a calibration standard. Reported values are approximate and should therefore be considered approximate.

FT-IR Spectroscopy Infrared spectrum is from Shimadzu IR Prestage-21 equipped with a black coated heated wire beam source, germanium coated on a potassium bromide (KBr) beam splitter, and a sensitive pyroelectric detector (DLATGS). Obtained with (FT-IR) spectrophotometer. Each spectrum represents 40 simultaneous additional scans collected with a spectral resolution of 4 cm ⁻¹ . Sample preparation consists of placing a KBr disc made from the sample and KBr. A background data set is obtained with a blank disc of KBr containing no sample. A LogMR (R = reflectance) spectrum is obtained by taking the ratio of these two data sets to each other. Wavelength calibration is performed using polystyrene. Reported values are approximate and should therefore be considered approximate.

Hygroscopicity test by dynamic vapor sorption analysis (DVS) The hygroscopicity test is performed using the surface measurement system DVS-1. Samples are placed on a microbalance in the instrument and monitored for weight changes during the adsorption / desorption cycle at 25 ° C. One sorption / desorption program consists of a 0-95% relative humidity (RH) adsorption scan and a 95-10% RH desorption scan. The other consists of an adsorption scan at 40-95% RH and a desorption scan at 95-0% RH, followed by a second adsorption scan at 0-40% RH. Both programs are run in 5% RH increments and allow the sample to equilibrate for 360 minutes or until equilibration is achieved at each step. At the end of the DVS experiment, the sample is measured by PXRD.

Nuclear magnetic resonance (NMR)
NMR data are 270 MHz (JEOL JNM-LA 270 spectrometer) or 300 MHz (JEOL JNM-LA 300) using deuterated chloroform (99.8% D) or dimethyl sulfoxide (99.9% D) as solvent unless otherwise stated. The data is shown in parts per million (ppm) with respect to tetramethylsilane (TMS) as an internal standard. Common abbreviations used are s = single line, d = double line, t = triple line, q = quadruple line, m = multiple line, br = broad.

High performance liquid chromatography (HPLC) measurement
HPLC data is obtained with a Waters Alliance 2695 HPLC system equipped with a 2996 PDA detector using the following conditions.
Column: Inertsil ODS-3 (3 μm, 4.6 x 150 mm),
Eluent: acetonitrile / 10 mM ammonium acetate = 32: 68
Detection: UV at 215 nm,
Flow rate: 1 mL / min, and column temperature: 40 ° C.
Data processing is performed using Empower 2 software supplied by Waters.

  The chemical symbols have the usual meanings of M (mol / liter), L (liter), mL (milliliter), g (gram), mg (milligram), mol (mol), mmol (mmol).

Example 1
2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine- Preparation of 5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide This compound is synthesized according to the conventional method described in WO97 / 024369.

Example 2
2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine- Preparation of 5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide This compound is synthesized according to the conventional method described in EP-1031575.

Example 3
L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c Preparation of polymorph Form I of] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide 2-amino-N- [obtained by the method of Example 1 2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- A mixture of (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide (1.0 molar equivalent) is dissolved in ethyl acetate. The organic layer is extracted with purified water and / or filtered. Add a solution of L-tartaric acid (1.0 molar equivalent) in methanol and mix. The solution is heated and methanol / ethyl acetate is removed by distillation. Isopropanol is added and the resulting solution is heated to reflux to convert to the desired polymorph. The solid is isolated, washed and dried under vacuum to give the salt of the title compound.
Using a solution of L-tartaric acid in isopropanol instead of methanol gives identical crystals with the following characteristics:
Melting point (DSC onset): 177 ° C.
Crystallinity by PXRD: Crystal (FIG. 1). Major peaks at 2-θ °: 4.4, 10.2, 12.5, 13.2, 13.7, 16.4, 16.6, 18.5, 19.3 and 21.7. Each peak has an error range of +/− 0.2.
MS (FAB) m / z: with additional peaks observed at 506 (M + H) ⁺ , m / z 421, 263, and 244.
IR (KBr): 3349, 3107, 3036, 2983, 2870, 2770, 2526, 1705, 1662, 1625, 1531, 1454, 1442, 1220, 1132, 1109, 1089 and 704 cm ⁻¹ .
Elemental analysis, calculated for C28H35N5O4 C4H6O6: C, 58.6; H, 6.3; N, 10.7. Observed: C, 58.6; H, 6.4; N, 10.8.

Example 4
[Hygroscopic test]
In the hygroscopicity test by dynamic vapor sorption (DVS) analysis, polymorph Form I is less than 2% moisture increase at 25 ° C., 40%, 80%, and 90% relative humidity (RH); Good results are shown compared to the compound prepared in Example 2.

Example 5
[Stability test]
For solid-state stability testing, use Nagano Science Constant temperature / humidity control chamber LH-20-11M, LH-21-11M, LTL-200D3CJ-14 or LTX-01. To do. The sample is placed in a chamber and exposed under 25 ° C./60% RH, 40 ° C./75% RH and / or xenon lamp irradiation. After exposure or irradiation, the crystalline morphology, thermal behavior, purity and / or weight change of the obtained samples are evaluated by XRPD, TG / DTA or DSC, HPLC, microbalance, respectively.
It can be seen that polymorph Form I is stable compared to the compound prepared in Example 2.

Example 6
[Solubility test]
Polymorph Form I exhibits good solubility (> 300 mg / mL) in aqueous buffer at pH 5 or lower.

Example 7
[Light stability test]
Samples for light stability of 25 ° C / 60% RH and 40 ° C / 75% RH samples stored in open pans with quartz glass covers and open round amber glass bottles covered with gauze Save to the second set.
In summary, there is no significant change in appearance, X-ray diffraction pattern, or infrared spectrum during storage of Polymorph Form I for 3 months. Over 3 months, no significant loss of titer is observed for any of the stability samples.

Claims (11)

  Use CuKα radiation with major peaks at 2-θ ° including 4.4, 10.2, 12.5, 13.2, 13.7, 16.4, 16.6, 18.5, 19.3 and 21.7 (where each peak has an error range of +/- 0.2 °) L-tartaric acid 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2, characterized by the powder X-ray diffraction pattern (PXRD) obtained upon irradiation] Polymorphic form of 3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide I.   The L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2 of claim 1 further characterized by differential scanning calorimetry (DSC) showing an endothermic event at about 177 ° C -Methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo- Polymorph form I of ethyl] -isobutyramide. 3349, 3107, 3036, 2983, 2870, 2770, 2526, 1705, 1662, 1625, 1531, 1454, 1442, 1220, 1132, 1109, 1089, and 704 cm ^-1 (where each peak is +/- 2 cm ^The 2-amino-N- [2-L-tartrate L-tartrate of claim 1 or 2, further characterized by an infrared (IR) spectrum (KBr) exhibiting an absorbance band at an error range of ^-1 (3a- (R) -Benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R ) -Benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph I.   L-tartaric acid 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a) according to any one of claims 1 to 3 , 4,6,7-Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients.   L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-] according to any one of claims 1 to 3 for use as a medicament 2,3,3a, 4,6,7-Hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide Form I.   L-Tartrate 2-amino-N according to any one of claims 1 to 3 in the manufacture of a medicament for curative, palliative or prophylactic treatment of pathological conditions mediated by ghrelin receptor activity -[2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl)- Use of the polymorph Form I of 1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide, or the pharmaceutical composition according to claim 4. A method for the treatment of a pathological condition mediated by ghrelin receptor activity, wherein an effective amount is applied to a non- human animal in need of such treatment as claimed in any one of claims 1-3. 2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridine tartrate -5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide polymorph Form I, or a method comprising administering a pharmaceutical composition according to claim 4.   2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3- c) pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide under conditions of L-tartaric acid in alcohol. L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro described in any one of A process for preparing polymorph Form I of -pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide.   2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3- c) pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide, subjecting to conditions of L-tartaric acid in methanol or isopropyl alcohol. L-Tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo described in Item 8 A process for preparing polymorph Form I of [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide.   2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4, to an alcohol selected from methyl alcohol, ethyl alcohol, and isopropyl alcohol Comprising exposing 6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide. 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7, L-tartaric acid described in any one of 3] Process for preparing polymorph Form I of -hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide.   2-Amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3- c) pyridin-5-yl) -1- (R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide, comprising the step of exposing L-tartrate 2-amino-N- [2- (3a- (R) -benzyl-2-methyl-3-oxo-2,3,3a, 4,6,7-hexahydro-pyrazolo [4,3-c] pyridin-5-yl) -1 A process for preparing polymorph Form I of-(R) -benzyloxymethyl-2-oxo-ethyl] -isobutyramide.

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